AMP-Deaminase Isoform E and Erythrocyte Metabolic Dysregulation in Sickle Cell Disease

Project Description Narrative:

---

An estimated 300,000 children are born each year worldwide with sickle cell disease, and one in 12 African Americans has sickle cell trait. The Wisconsin Sickle Cell Disease Comprehensive Center serves approximately 400 children and young adults with sickle cell syndromes, which reflects a significant health issue to the people of Wisconsin.

AMP deaminase (AMPD) is a highly regulated enzyme that catalyzes a pivotal reaction in the purine nucleotide catabolic and interconversion pathways. Whereas most human tissues and cells express more than one member of the AMPD gene family, erythrocytes contain only one AMPD enzyme—isoform E, which is also uniquely activated by Ca2+-calmodulin. Erythrocytes are characterized by the developmental loss of an enzyme in the IMP to AMP branch point pathway and must keep isoform E in a relative inactive state in order to prevent the irreversible depletion of the adenine nucleotide pool during periods of energy imbalance. This project will investigate the hypothesis that an activated isoform E contributes to erythrocyte metabolic dysregulation of sickle cell disease, which exhibits a disturbed calcium homeostasis that leads to cell dehydration.

The research findings from this project could be translated into improved health of Wisconsin residents affected by sickle cell disease.